Organic nitrates, like glycerol trinitrate (GTN) (Murrel, Lancet: 80, 113, 151 (1879)), pentaerythrityl tetranitrate (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958), U.S. Pat. No. 2,370,437), isosorbide-5-mononitrate (ISMN) (DE-OS 22 21 080, DE-OS 27 51 934, DE-OS 30 28 873, DE-PS 29 03 927, DE-OS 31 02 947, DE-OS 31 24 410, EP-PS 45 076, EP-PS 57 847, EP-PS 59 664, EP-PS 64 194, EP-PS 67 964, EP-PS 143 507, U.S. Pat. No. 3,886,186, U.S. Pat. No. 4,065,488, U.S. Pat. No. 4,417,065, U.S. Pat. No. 4,431,829), isosorbide dinitrate (ISDN) (L. Goldberg, Acta Physiology. Scand, 15, 173 (1948)), propatyl nitrate (Medard, Mem. Poudres 35: 113 (1953)), trolnitrate (FR-PS 984 523) or nicorandil (U.S. Pat. No. 4,200,640) and similar compounds are vasodilators, which have found extensive therapeutic use for decades chiefly in the indication angina pectoris and ischemic heart disease (IHD) (Nitrangin.RTM., Pentalong.RTM., Monolong.RTM., Isoket.RTM., Elantan.RTM. and others). Organic nitrates of new types, for example, SPM 3672 (N-[3-nitratopivaloyl]-L-cysteine ethyl ester) (U.S. Pat. No. 5,284,872), as well as its derivatives exhibit, comparable and improved pharmacological efficacy when used in the aforementioned indications. The use of organic nitrites, like isoamyl nitrite, as coronary dilator has also long been known (Brunton, Lancet, 97 (1867)). Other NO-liberating or transferring compounds, like thionitrites, thionitrates, S-nitrosothiols or nitrosoproteins (Harrison et al., Circulation, 87:1461-1467 (1993), as well as substituted furoxanes (1,2,5-oxadiazole-2-oxide, furazan-N-oxide) (Feelisch al., Biochem. Pharmacol. 44:1149-1157 (1992) or substituted sydnonimines, especially molsidomine (DE-AS 16 95 897, DE-AS 25 32 124, DD-PS 244 980), are also described as potent coronary dilators. All these substances themselves or in the form of pharmacologically active metabolites, for example, the molsidomine metabolites SIN 1 and SIN 1A (Noack Nitroglycerin VII, Walter de Gruyter & Co., Berlin, 1991, 23-28), as well as their derivatives and structural analogs (Noack and Feelisch, Molecular mechanism of nitrovascular bioactivation, in "Endothelial Mechanisms of Vasomotor Control" (editors Drexler et al.), pp. 37-50, Steinkopff Verlag, Darmstadt, FRG (1991)), are capable of in vivo liberation or transfer of nitric oxide.
The galenic processing of organic nitrates and nitrites, as well as other NO-liberating or transferring compounds to pharmaceutical preparation for treatment of angina pectoris and ischemic heart disease is generally known. It occurs according to procedures and rules generally familiar to pharmaceutical experts, in which selection of the technologies to be applied and the galenic auxiliaries to be employed is primarily guided according to the active principle being processed. Questions of chemical-physical properties, the chosen form of administration, the desired effect time, as well as avoidance of drug auxiliary incompatibilities are of special significance here. Peroral, parenteral, sublingual or transdermal administration in the form of tablets, coated tablets, capsules, solutions, sprays or plasters is primarily described for drugs with the indication angina pectoris and ischemic heart disease (DD-PS 293 492, DE-AS 26 23 800, DE-OS 33 25 652, DE-OS 33 28 094, DE-PS 40 07 705, DE-OS 40 38 203, JP Application 59/10513 (1982)).
In addition to the applications of nitrosylating substances that have been known for years, their use to treat and prevent diseases caused by pathologically increased concentrations of sulfur-containing amino acids in body fluids is also described. These disease entities, caused by congenital or acquired defects in metabolism of these amino acids and characterized by increased blood and urine concentrations of said amino acids (homocystinuria), are combined under the term homocysteinemia [sic] .sup.* (WO 92/18002).
The antiischemic effectiveness of organic nitrates and the other aforementioned substance classes is explained by hemodynamic effects, especially a heart-unloading effect that leads to economy of oxygen consumption of the heart or corrects the imbalance between O.sub.2 supply and demand present in IHD. The cause is preferred expansion of venous pooling and a reduction in preload with a direct coronary dilatation effect, especially in the area of coronary stenosis. The post-stenotic reduced perfusion could be favorably influenced precisely by this (positive steal effect) since the organic nitrates obviously have a more potent effect in atherosclerotic vessels than in healthy vessels (Koida et al., Endothelium 1 (supplement): Abstract 299, p. s76 (1993)), especially in the area of coronary stenoses. This purely hemodynamic effect is mediated by radical nitric oxide (NO.multidot.), which is uniformly liberated from all nitrovasodilators despite the very different chemical structure of the compounds. The bioactivation pathways that ultimately lead to production of NO.multidot. in situ, i.e., in the endothelial cells and smooth muscle cells of the vessel, are very different, however (Noack and Feelisch, Molecular mechanism of nitrovascular bioactivation, in: "Endothelial Mechanisms of Vasomotor Control" (editors Drexler et al.), pp. 37-50, Steinkopff Verlag, Darmstadt, FRG (1991)). This was clarified beyond question in recent years by direct NO measurement by different techniques (method of Noack et al., Neuroprotocols, 1:133-139 (1992)). NO has a vasodilatory effect by activating soluble guanylate cyclase. Formation of cGMP from GTP is stimulated by this. cGMP in turn leads to various phosphorylation reactions (e.g., on protein kinases) that promote intracellular Ca storage (Karczewski et al., Z. Kardiol. 79 (supplement 1):212 (1990)). Relaxation then occurs from the reduction in intracellular free Ca.sup.2+ level. It has been known since 1987 that the endothelium derived relaxing factor (EDRF) is identical to NO or an NO-containing substance (Palmer et al., Nature, 327:524-526 (1987); Ignarro et al., Proc. Natl. Acad. Sci. 84, 9265-9269 (1987)) and has important significance for local blood supply. FNT .sup.* [Translator's note: homocystinemia?]
The endothelial cells form a continuous monolayer in the region of the internal wall of a blood vessel. This results in a total surface of about 800 m.sup.2 for an adult person with an intrinsic weight (1.5 to 2 kg) corresponding to that of the human liver. According to the present view, the functions exerted by the endothelial cells are of two kinds: mechanical and functional. On the one hand, they exert a sort of barrier function with which penetration of blood components, like low-density lipoproteins (LDL), into the vessel wall near the lumen (intima) is supposed to be prevented. On the other hand, they possess an endocrine function. Increased synthesis of bioactive substances occurs from different stimuli, like EDRF/NO and prostaglandin-I.sub.2 (PGI.sub.2) with which the function of the flowing cells (Pohl and Busse, Eur. Heart J., 11 (supplement B), 35-42 (1990)) regional hemodynamics (Furchgott, Circ. Res. 53:557-573 (1983)) and the structure of the vessel wall (Di Corleto, Exp. Cell Res. 153:167-172 (1984)) are fundamentally influenced. The fact that a pathological effect on endothelial function that can have different consequences invariably occurs during damage to the endothelium for any reason (endothelial damage from hypercholesterolemia (T. J. Verbeuren et al., Circ. Res. 58:552-564 (1986)), endothelial damage in the postinfarction phase (M. R. Sigreid et al., Circ. 86 (supplement 1) :21 (1992)) is thus explained informally at the same time. Regional vasoconstriction and vasospasm and reconstruction or growth processes in the vessel wall that are viewed as initial processes of atherogenesis are included here.
Endothelial dysfunction is generally characterized by a limitation or loss of physiological vasodilation mediated by the endothelium. A reduction or increase in NO-mediated vessel relaxation, vascular protection mediated by NO and growth processes suppressed by NO in the intima and media is observed simultaneously. Endothelial dysfunction is also characterized by proliferative processes in the vessel wall as a result of increased mitogenesis, increased endothelial adhesion and migration of leukocytes and macrophages, as well as increased oxidation of low density lipoproteins (LDL), which damage the endothelium. It is regularly observed in pathophysiological states within the scope of atherosclerosis, hypertension, hypercholesterolemia, diabetes mellitus and cardiac insufficiency (Creager et al., J. Clin. Invest. 86, 228-234 (1990); Linder et al., Circulation 81:1762-1769 (1990); Zeiher et al., Circulation 83:391-401 (1991)). Hypoxia and limited shear forces are also triggering events for an endothelial dysfunction. Among other things, it leads to a situation in which vasoactive substances, like acetylcholine or serotonin, which normally produce vasorelaxation, cause vasoconstriction because of their direct vasoconstrictive effects on smooth vascular musculature, which adversely affects the disease picture (Golino et al., N. Engl. J. Med. 324:641-648 (1991)). Physiological vasomotor regulation is therefore not just disturbed during endothelial dysfunction, but in fact reversed. These changes are even more pronounced during atherosclerotic reconstruction of the internal wall of the vessel (Ludmer et al., N. Engl. J. Med. 315:1046-1051 (1986)).
With its autocrine and paracrine activity, the endothelium contributes not only to maintaining health of the wall of the blood vessel, but also influences the effect of exogenous NO liberators, like PETN or GTN, by forming EDRF/NO itself. If the endothelium is removed, for example, mechanically, from the wall of the artery (during invasive catheter diagnosis or extracorporeally on isolated vessel segments), or if endothelial NO formation is suppressed by specific inhibitors, the vasodilative effect of nitrovasodilators like GTN or PETN is intensified (Busse et al., Cardiovasc. Pharmacol. 14 (supplement 11) :S81-S85 (1989); Kojda et al., J. Vasc. Res. 29:151 (1992A)). Pharmacological inhibition of endothelial NO synthesis leads to the same effect on coronary veins (Kojda et al., Naunyn-Schmiedeberg Arch. Pharmacol. 346:R35 (1992B)). It is known that the effect of calcium antagonists, especially those of the 1,4-dihydropyridine type (DHPs), is weakened after removal of the endothelium (Kojda et al., Bas. Res. Cardiol. 86:254-256 (1991)). Further studies have shown that these substances are probably stimulators of endothelial NO formation and liberation (Gunther et al., Basic Res. Cardiol. 87:452-460 (1992)). Kinins, like bradykinins, also exert their biological activity via increased endothelial formation and liberation of EDRF/NO (V. A. Briner et al., Am. J. Physiol. 264:F322-F327 (1993); Kelm et al., Biochem. Biophys. Res. Commun. 154:236-244 (1988)).